This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The increasing prevalence of obesity is driving a surge in the incidence of associated metabolic diseases including insulin resistance, type 2 diabetes mellitus, hyperlipidemia, and non-alcoholic fatty liver disease (NAFLD). Perturbations in lipid homeostasis (secondary to fatty acid oversupply) play a primary role in the pathogenesis of each of these diseases. However, the mechanisms controlling key constituents of fatty acid metabolism remain to be discovered. The peroxisome proliferator-activated receptor (PPAR) coactivator 1 (PGC-1alpha) is a highly inducible coactivator that coordinates the capacity for hepatic mitochondrial fatty acid oxidation, oxidative phosphorylation, and gluconeogenesis via transcriptional activation of multiple targets in these metabolic pathways. PGC-1 plays an important role in both muscle and liver during metabolic maladies such as obesity and diabetes. In muscle, PGC-1 expression is decreased in insulin resistance consistent with inappropriate switching between fat and carbohydrate oxidation. Hepatic fatty acid homeostasis is modulated at the level of gene transcription by a family of nuclear receptor transcription factors, the peroxisome proliferator-activated receptors (PPARs) and their coactivator protein (PGC-1alpha). PGC-1alpha is a highly-inducible coactivator that regulates transcription factors controlling multiple energy metabolic pathways including gluconeogenesis, mitochondrial oxidative phosphorylation, fatty acid catabolism, and triglyceride synthesis and secretion.